Despite use of computed tomography, some lung cancer patients are found to have unresectable disease at surgery, or they present early with metastases. We studied whether whole-body positron emission tomography (PET) with 18F-fluorodeoxyglucose (18FDG) would improve the preoperative detection of metastases. We retrospectively analysed 34 patients with "operable" non-small-cell lung cancer who underwent 18FDG PET after routine assessment. Management changes produced by the PET scan and confirmatory tests were reviewed. PET identified unsuspected malignant lesions in 10 (29%) patients. Management changes occurred in 14 (41%), including 6 (18%) patients who were changed to non-surgical therapy. These data suggest that whole-body 18FDG PET improves preoperative assessment of lung cancer patients.

We studied whether spinal locomotor centres of patients with paraplegia can be activated by external stimuli. In patients with complete paraplegia, coordinated stepping movements were induced by weight support and standing on a moving treadmill. The pattern of leg muscle electromyographic (EMG) activity was similar to that seen in healthy subjects although EMG amplitude was smaller. With daily training the amplitude of gastrocnemius EMG activity increased during weight-bearing phase of stepping and the degree of inappropriate tibialis anterior activity decreased. Patients with incomplete paraplegia profited from the training programme in that their walking on a stationary surface improved even when unsupported. Our results may suggest new ways to improve mobility of patients with paraplegia.

Very few patients with liver metastases from colorectal cancer can be cured. We have investigated whether a treatment to slow the growth of liver metastases, hepatic-artery infusion of floxuridine, improves palliation in this setting. In a randomised study of 100 patients, we compared quality of life and survival in patients who received hepatic-artery infusion of floxuridine and in those who received conventional symptom palliation. 95% of control patient survival time was spent with normal quality-of-life scores, which suggests that the aim of treatment should be to prolong normal-quality survival rather than merely to sustain quality of life. There was a significant prolongation (p = 0.03) in overall survival in floxuridine-treated patients compared with controls (median 405 vs 226 days). There were similar significant prolongations in normal-quality (ie, normal symptom scores) survival for physical symptoms (p = 0.04), anxiety (p = 0.04), and depression (p = 0.04). This survival benefit was associated with significant reductions in metastasis size on computed tomography (p = 0.001) and in serum carcinoembryonic antigen concentration (p = 0.006) in floxuridine-treated patients. There was no evidence of treatment-related hepatotoxicity as assessed by serum aspartate aminotransferase and bilirubin measurements. This is the first demonstration that survival can be prolonged with normal quality of life in patients with colorectal liver metastases. We conclude that hepatic-artery floxuridine infusion can be recommended for suitable patients.

Diagnostic tests that are hazardous or infeasible, or both, may become accepted before inadequacies are recognised; only multicentre trials can provide the necessary information for an unrestricted acceptance of any new diagnostic procedure. We prospectively studied the results obtained in 24 experienced echocardiography laboratories. 2949 tests were done in 2799 patients. In 341 tests (12% of the overall population, 21% of the negative tests) the test could not be completed because of complex ventricular tachyarrhythmias (134, 38% of all submaximal studies); nausea and/or headache (71, 20%); hypotension and/or bradycardia (62, 17%); supraventricular tachyarrhythmias (44, 12%); hypertension (24, 7%); and others (20, 6%). Dangerous events (life-threatening complications or side-effects requiring specific treatment and lasting more than 3 hours, or new hospital admission) occurred in 14 cases (1 every 210 tests)--9 cardiac (3 ventricular tachycardias; 2 ventricular fibrillations; 2 myocardial infarctions; 1 prolonged antidote-resistant myocardial ischaemia; 1 severe, persistent hypotension) and 5 extracardiac (atropine poisoning with hallucinations lasting several hours in the absence of either myocardial ischaemia or hypotension). Life-threatening and/or longlasting complications may occur during dobutamine/atropine stress echocardiography. The test is generally well tolerated, although may be interrupted by minor, self-limiting, usually symptomless side-effects.

Lipid-lowering therapy ameliorates coronary atherosclerosis in patients with raised concentrations of low-density-lipoprotein (LDL) cholesterol. We have investigated whether a similar benefit can be obtained in normocholesterolaemic patients. We studied 79 normocholesterolaemic patients with coronary heart disease (70 male, 9 female), mean age 58 years, all non-smokers, with mean total cholesterol concentration 5.5 mmol/L. All patients received diet therapy and were randomly assigned placebo (39) or active treatment (40) with pravastatin, nicotinic acid, cholestyramine, and gemfibrozil stepwise as needed to reach the specified goal (total cholesterol < or = 4.1 mmol/L, ratio of LDL/high-density-lipoprotein [HDL] cholesterol < or = 2.0). Coronary angiograms at baseline and after 2.5 years of treatment were analysed by computer-assisted quantitative techniques. There was no significant difference in coronary atherosclerosis during follow-up between the active treatment and placebo groups; the mean minimum diameter narrowed significantly but to the same extent in both groups (change baseline to 2.5 years 0.14 [SD 0.42] and 0.15 [0.42] mm, respectively, both p < 0.001). Similarly, the change in percentage stenosis did not differ between the groups (2.1 [10.6] vs 2.4 [10.3]%). By multiple regression analysis, the adjusted difference between the groups was a 0.04 mm (95% CI -0.04 to 0.12 mm) increase in minimum diameter and a 0% (-1.7 to 1.7) change in percentage stenosis. The groups differed significantly in plasma lipids (% change in active minus % change in placebo group: -28% total cholesterol, -41% LDL-cholesterol, 13% HDL-cholesterol, -26% triglycerides, -31% apolipoprotein B, all p < 0.001). Thus, intensive pharmacological treatment of normocholesterolaemic patients has significant effects on plasma lipid concentrations but no angiographically measurable benefit on the coronary arteries.

Effective, safe antimalarial vaccines have proved elusive. The synthetic polypeptide SPf66 vaccine is based on preerythrocytic and asexual blood-stage proteins of Plasmodium falciparum. We report here a randomised double-blind placebo-controlled trial of the efficacy of the SPf66 vaccine against clinical P falciparum malaria in idete, southern Tanzania, an area of intense perennial malaria transmission. 586 children aged 1-5 years received three doses of vaccine (n = 274) or placebo (n = 312). The incidence and density of parasitaemia were assessed through repeated cross-sectional surveys on subgroups of children. Morbidity was monitored over a 1 year period through passive case detection in all children plus active case detection in a subgroup of 191. An episode of clinical malaria was defined as measured fever (> or = 37.5 degrees C) and parasite density > 20,000/microL. No severe side-effects were seen and the frequency of mild side-effects after the third dose was less than 6%. The vaccine was highly immunogenic and after three doses all vaccine recipients had detectable anti-SPf66 antibodies: the geometric mean index of response was 8.3 in the vaccine group and 0.7 in the placebo group. The incidence of parasitaemia was similar in both groups. 123 children had at least one episode of clinical malaria during the follow-up period after the third dose and annual incidence rates were 0.25 in the vaccine group and 0.35 in the placebo group. Estimated vaccine efficacy was 31% (95% confidence interval 0-52%; p = 0.046). After the third dose there were 6 deaths among the study cohort (1 vaccine, 5 placebo). This study confirms that SPf66 is safe, immunogenic and reduces the risk of clinical malaria among children exposed to intense P falciparum transmission.

Botulinum toxin can chemically denervate striated muscle. Botulinum toxin A (15 U) was used to treat ten patients with chronic anal fissure by injection in the internal sphincter. In seven patients, the lesion healed at 2 months after treatment; one relapsed at 3 months. In one patient the lesion healed at 1 month, but partly relapsed a month later. Mild faecal incontinence lasting for 1 day was observed in one patient. We propose that botulinum toxin injections in the internal anal sphincter be considered an alternative approach to surgical therapy of anal fissure.

Our in-vitro, animal, and early clinical data suggest that tumour necrosis factor alpha (TNF alpha) is an important target for specific biological therapy in rheumatoid arthritis. We report the results of repeated treatment with a chimeric monoclonal antibody to TNF alpha (cA2) in patients having disease flares. 7 patients originally enrolled in an open-label trial completed two to four cycles, each of which was followed by a good clinical response, with median improvements in the swollen-joint count and C-reactive protein exceeding 80%. cA2 may be useful therapy in the control of acute disease flares in rheumatoid arthritis and treatment programmes including cA2 may be effective in the long-term management of this disease.

Tumour necrosis factor alpha (TNF alpha) is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy. In support of this hypothesis, we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha (cA2). We now report the results of a four-centre, randomised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis. The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, an amalgam of six clinical, observational, and laboratory variables. Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time, compared with 11 of 25 patients treated with low-dose cA2 (p = 0.0083) and 19 of 24 patients treated with high-dose cA2 (p < 0.0001). Over half of the high-dose cA2 patients responded by the more stringent 50% Paulus criteria at this time (p = 0.0005). The magnitude of these responses was impressive, with maximum mean improvements in individual disease-activity assessments, such as tender or swollen-joint counts and in serum C-reactive protein, exceeding 60% for patients on high-dose treatment. There were two severe adverse events. 1 patient on 1 mg/kg cA2 developed pneumonia ("possibly" treatment-related) and 1 on 10 mg/kg had a fracture ("probably not" treatment-related). The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis.

Acute diarrhoea is a serious cause of infant morbidity and mortality, and the development of preventive measures remains an important goal. Bifidobacteria (which constitute the predominant intestinal flora of breastfed infants), as well as other lactic-acid-producing organisms such as Streptococcus thermophilus, are thought to have a protective effect against acute diarrhoeal disease. However, their efficacy has not been assessed in controlled trials. In a double-blind, placebo-controlled trial, infants aged 5-24 months who were admitted to a chronic medical care hospital were randomised to receive a standard infant formula or the same formula supplemented with Bifidobacterium bifidum and S thermophilus. Patients were evaluated daily for occurrence of diarrhoea, and faecal samples, obtained weekly, were analysed for rotavirus antigen by enzyme immunoassay. Faecal samples were also obtained during an episode of diarrhoea for virological and bacteriological analyses. 55 subjects were evaluated for a total of 4447 patient-days during 17 months. 8 (31%) of the 26 patients who received the control formula and 2 (7%) of 29 who received the supplemented formula developed diarrhoea during the course of the study (p = 0.035, Fisher's exact test, two-tailed). 10 (39%) of the subjects who received the control formula and 3 (10%) of those who received the supplemented formula shed rotavirus at some time during the study (p = 0.025). The supplementation of infant formula with B bifidum and S thermophilus can reduce the incidence of acute diarrhoea and rotavirus shedding in infants admitted to hospital.

The role of iron supplementation in treating the anaemia of systemic-onset juvenile chronic arthritis is not clear. Eight affected children with severe persistent anaemia unresponsive to oral iron therapy were treated with intravenous iron saccharate. From a median post-oral-iron value of 8.0 g/dL (range 6.5-9.5), haemoglobin rose to 11.0 g/dL (10.1-12.1) (p = 0.01). The concentration of serum transferrin receptor, an indicator of iron deficiency, before intravenous therapy correlated with the increase in haemoglobin (r = 0.88, p < 0.01). Intravenous iron saccharate could be an effective treatment for chronic anaemia in this condition, especially with iron deficiency not responsive to oral iron.

We studied the involvement of naturally occurring odours in guiding the baby to the nipple. One breast of each participating mother was washed immediately after delivery. The newborn infant was placed prone between the breasts. Of 30 infants, 22 spontaneously selected the unwashed breast. The washing procedure had no effect on breast temperature. We concluded that the infants responded to olfactory differences between the washed and unwashed breasts.

3-5% of patients taking the 5HT1D agonist sumatriptan for migraine have chest discomfort, suggesting a cardiac origin. We have investigated an alternative explanation of an oesophageal cause in 24 volunteers after the subcutaneous administration of a supratherapeutic dose of sumatriptan (16 mg) or placebo in a randomised, double-blind crossover study. Sumatriptan did not alter the electrocardiogram but increased the amplitude (p < 0.001) and duration (p < 0.001) of oesophageal contractions without affecting velocity of propagation. Clinically abnormal motility was also increased (p = 0.001), and was more common in the 5 subjects with chest pain after sumatriptan. The effect of sumatriptan on oesophageal function provides an alternative explanation for the chest symptoms.

Current regimens of sequential hormone replacement therapy are based on data that show a protective effect on the endometrium of at least 10 days of progestagen. In clinical practice, onset of bleeding on or after day 11 of the progestagen phase is taken as reassurance of a normal endometrium. 413 postmenopausal women taking oestrogen-progestagen hormone replacement therapy with 10 or 12 days of progestagen per cycle completed bleeding diaries for 3 months before endometrial biopsy. For most women, bleeding started around the 13th day after starting progestagen. There was no correlation between endometrial histology and timing of onset of bleeding. 11 (2.7%) women had complex endometrial hyperplasia. The prevalence of hyperplasia was 2.4% with 10 days of progestagen per cycle and 2.8% with 12 days [corrected]. The timing of onset of withdrawal bleeding during oestrogen-progestagen HRT does not predict endometrial hyperplasia.

For some patients with coronary artery disease, percutaneous transluminal coronary angioplasty (PTCA) is an alternative to coronary artery bypass grafting (CABG). We report comparative health service costs of these interventions within the Randomised Intervention Treatment of Angina (RITA) trial. Medications were costed at published UK prices; other resource use was costed with a set of unit costs estimated at two recruiting centres to the RITA trial, one in London and one outside. Over 2-year follow-up of 1011 patients, the estimated mean additional cost for those randomised to CABG compared with PTCA was 1050 pounds (95% CI 621 pounds-1479 pounds), with unit costs from the non-London centre, and 1823 pounds (1202 pounds-2444 pounds), with unit costs from the London centre. The initial average cost of treating a patient randomised to PTCA is about 52% of that of CABG, but after 2 years this increased to about 80% because of the greater need for subsequent interventions. The balance of advantage between PTCA and CABG may change after several years: funding has been obtained to continue RITA follow-up for 10 years. However, on the basis of patients' status at 2 years, the cost advantages of PTCA cannot be ignored. Further research is necessary to assess whether the advantage of PTCA in terms of cost is translated into one of cost-effectiveness.

Low-molecular weight heparin has theoretical advantages over aspirin and dipyridamole in maintaining vascular-graft patency by virtue of its better antithrombotic effect and antiproliferative activity on vascular, smooth-muscle cells. We tested the hypothesis that low-molecular weight heparin would be more effective than aspirin and dipyridamole in maintaining graft patency in patients undergoing femoropopliteal bypass grafting. Patients were randomised to receive either a daily injection of 2500 IU low-molecular weight heparin, or 300 mg aspirin with 100 mg dipyridamole 8 hourly for 3 months. 94 patients were randomised to low-molecular weight heparin and 106 to aspirin and dipyridamole. Patients were stratified according to indication for surgery and were followed up for 1 year. Kaplan-Meier estimate of graft patency showed 87% graft survival on low-molecular-weight heparin and 72% on aspirin and dipyridamole at 6 months. At 12 months, the respective figures were 78% and 64%. Stratified survival analysis showed that this benefit was confined to those having salvage surgery (log rank test p = 0.0006); for those having surgery for claudication there was no significant benefit. No major bleeding events occurred in either group. We conclude that low-molecular weight heparin is better than aspirin and dipyridamole in maintaining femoropopliteal-graft patency in patients with critical limb ischaemia undergoing salvage surgery. This treatment should have considerable cost benefits.